PROJECT SUMMARY During nervous system development in vertebrates, newborn neurons migrate extensively to precise locations where they generate circuits that control behaviors and functions essential for health and survival. Defective migration of neurons in different regions of the human brain is associated with neuronal migration disorders that can lead to epilepsy, and cognitive and motor deficits. The long-term goal of this research is to understand the mechanisms by which neurons migrate so that the causes and potential remedies for human brain disorders can eventually be identified. The caudal migration of facial branchiomotor (FBM) neurons is an excellent model system to investigate neuronal migration mechanisms. A large number of genes, including several functioning the Wnt/Planar Cell Polarity (PCP) signaling pathway, are required for initiating or maintaining FBM neuron migration in zebrafish and mice. However, how FBM neurons choose to migrate in the caudal direction has remained a vexing mystery. Our published studies on the PCP cadherin Celsr1 and preliminary data have generated the first insights into the direction-sensing mechanism. We hypothesize that Celsr1 normally functions to block inappropriate, Wnt- and Disheveled (Dvl)-dependent, rostral migration of FBM neurons in mice. The specific aims will test several predictions of this model. Aim 1 will test whether FBM neuron migration toward rostrally-positioned Wnt5a beads is reduced in Dvl2 mutants. Aim 2 will test whether rostral migration of FBM neurons is suppressed in Celsr1; Wnt5a double mutants. Aim 3 will test whether rostral migration of FBM neurons is enhanced in Celsr1 mutants overexpressing Wnt5a. Successful completion of these studies will provide novel insight into the mechanisms by which FBM neurons choose the direction of migration, and establish a general mechanism that neurons can employ to migrate in a directed fashion.